While there is evidence that reorganization in the motor cortex of the hemisphere contralateral to the stroke (contralesional M1) will impact motor function of the paretic limb in the acute and chronic phase post-stroke, the extent and the precise events that specifically influence it and how it relates to recovery of motor function remain to be defined. A better understanding of contralesional M1 reorganization is critical to the future development of optimal therapeutic strategies such as non-invasive stimulation protocols to improve functional recovery following stroke. The objectives in this application are to define the factors that influence contralesional M1 reorganization, determine the extent of contralesional M1 reorganization and its role in motor recovery in the acute and chronic post-stroke period. In a longitudinal study of stroke patients, contralesional M1 reorganization and stimulation will be assessed in two Specific Aims. In the first Specific Aim, we will determine the extent of functional and structural contralesional M1 reorganization using complementary techniques of transcranial magnetic stimulation (TMS), functional and structural MRI of the brain and behavioral measures. In the second Specific Aim, the contribution of contralesional M1 reorganization to the recovery of motor function will be studied. Repetitive TMS (rTMS) will be used to transiently disrupt contralesional M1 function, thereby determine its role for the motor performance of the paretic limb. RTMS related improvement of motor performance would identify a supportive role of contralesional M1 while deterioration of motor performance would indicate its detrimental role. In addition we will explore biomarkers that can determine the role contralesional M1 in the recovery process. At the completion of this project, it is our expectation that we will have identified the extent to which contralesional M1 activity determines motor performance during the acute and chronic phases of post-stroke recovery and can be targeted by interventions depending on its state (role) in the recovery process. This latter knowledge would be expected to have a substantial positive impact on the design of future evidence based treatment protocols for stroke patients that will significantly improve functional recovery.